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CSMD3 Deficiency Leads to Motor Impairments and Autism-Like Behaviors via Dysfunction of Cerebellar Purkinje Cells in Mice
Journal of Neuroscience ( IF 4.4 ) Pub Date : 2023-05-24 , DOI: 10.1523/jneurosci.1835-22.2023
Ke Xi 1, 2, 3 , Si-Qing Cai 1, 2, 3 , Hui-Fang Yan 4 , Yue Tian 1, 2, 3 , Jie Cai 1, 2, 3 , Xiao-Mei Yang 5 , Jing-Min Wang 6 , Guo-Gang Xing 2, 3, 7, 8
Affiliation  

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with highly heritable heterogeneity. Mutations of CUB and sushi multiple domains 3 (CSMD3) gene have been reported in individuals with ASD. However, the underlying mechanisms of CSMD3 for the onset of ASD remain unexplored. Here, using male CSMD3 knock-out (CSMD3–/–) mice, we found that genetic deletion of CSMD3 produced core autistic-like symptoms (social interaction deficits, restricted interests, and repetitive and stereotyped behaviors) and motor dysfunction in mice, indicating that the CSMD3 gene can be considered as a candidate for ASD. Moreover, we discovered that the ablation of CSMD3 in mice led to abnormal cerebellar Purkinje cell (PC) morphology in Crus I/II lobules, including aberrant developmental dendritogenesis and spinogenesis of PCs. Furthermore, combining in vivo fiber photometry calcium imaging and ex vivo electrophysiological recordings, we showed that the CSMD3–/– mice exhibited an increased neuronal activity (calcium fluorescence signals) in PCs of Crus I/II lobules in response to movement activity, as well as an enhanced intrinsic excitability of PCs and an increase of excitatory rather than inhibitory synaptic input to the PCs, and an impaired long-term depression at the parallel fiber–PC synapse. These results suggest that CSMD3 plays an important role in the development of cerebellar PCs. Loss of CSMD3 causes abnormal PC morphology and dysfunction in the cerebellum, which may underlie the pathogenesis of motor deficits and core autistic-like symptoms in CSMD3–/– mice. Our findings provide novel insight into the pathophysiological mechanisms by which CSMD3 mutations cause impairments in cerebellar function that may contribute to ASD.

SIGNIFICANCE STATEMENT Autism spectrum disorder (ASD) is a neurodevelopmental disorder with highly heritable heterogeneity. Advances in genomic analysis have contributed to numerous candidate genes for the risk of ASD. Recently, a novel giant gene CSMD3 encoding a protein with CUB and sushi multiple domains (CSMDs) has been identified as a candidate gene for ASD. However, the underlying mechanisms of CSMD3 for the onset of ASD remain largely unknown. Here, we unravel that loss of CSMD3 results in abnormal morphology, increased intrinsic excitabilities, and impaired synaptic plasticity in cerebellar PCs, subsequently leading to motor deficits and ASD-like behaviors in mice. These results provide novel insight into the pathophysiological mechanisms by which CSMD3 mutations cause impairments in cerebellar function that may contribute to ASD.



中文翻译:

CSMD3 缺陷通过小鼠小脑浦肯野细胞功能障碍导致运动障碍和自闭症样行为

自闭症谱系障碍(ASD)是一种具有高度遗传异质性的神经发育障碍。据报道,自闭症谱系障碍 (ASD) 个体中存在CUB 和 sushi 多域 3 ( CSMD3 ) 基因突变。然而,CSMD3 引发 ASD 的潜在机制仍未被探索。在这里,我们使用雄性CSMD3敲除 ( CSMD3 –/– ) 小鼠,发现CSMD3的基因缺失在小鼠中产生了核心的自闭症样症状(社交互动缺陷、兴趣受限、重复和刻板行为)和运动功能障碍,这表明CSMD3基因可以被认为是自闭症谱系障碍候选基因。此外,我们发现小鼠中CSMD3的消除导致小腿 I/II 小叶中小脑浦肯野细胞 (PC) 形态异常,包括 PC 发育树突发生和棘发生异常。此外,结合体内纤维光度钙成像和离体电生理记录,我们发现CSMD3 –/–小鼠的 Crus I/II 小叶 PC 中的神经元活动(钙荧光信号)表现出增加,以响应运动活动,以及PC 的内在兴奋性增强,PC 的兴奋性而非抑制性突触输入增加,以及平行纤维-PC 突触的长期抑制受损。这些结果表明CSMD3在小脑PC的发育中发挥重要作用。CSMD3 的缺失会导致小脑 PC 形态异常和功能障碍,这可能是CSMD3 –/–小鼠运动缺陷和核心自闭症样症状的发病机制。我们的研究结果为CSMD3突变导致小脑功能损伤(可能导致自闭症谱系障碍)的病理生理机制提供了新的见解。

意义声明自闭症谱系障碍 (ASD) 是一种具有高度遗传异质性的神经发育障碍。基因组分析的进步促成了许多与自闭症谱系障碍风险相关的候选基因。最近,编码具有CUB和sushi多结构域(CSMD)的蛋白质的新型巨基因CSMD3被确定为自闭症谱系障碍(ASD)的候选基因。然而, CSMD3引起 ASD的潜在机制仍然很大程度上未知。在这里,我们揭示了CSMD3的缺失会导致小脑 PC 的形态异常、内在兴奋性增加和突触可塑性受损,从而导致小鼠的运动缺陷和 ASD 样行为。这些结果为CSMD3突变导致小脑功能损伤(可能导致自闭症谱系障碍)的病理生理机制提供了新的见解。

更新日期:2023-05-25
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